The sympathetic branch of the autonomic system is a key regulator of blood pressure. Catecholamine secretory vesicles release co-stored transmitters by exocytosis into the bloodstream or synaptic clefts, where they contact cardiovascular target cells. In addition to catecholamines, the secretory "quantum" includes neuropeptides and chromogranins, precursors of active peptides mediating vascular responses to sympathoadrenal activation, and hence blood pressure. Our central theme is: Genetic variation and sympathoadrenal co-transmitters in blood pressure regulation. This Program links 5 Projects to study biosynthesis, release, and actions (pre- and post-synaptic) of these transmitters, integrating their effects on blood pressure. Central themes focus interactive/synergistic efforts. Projects 1&2 include human studies, and Projects 2&5 probe mechanisms in transgenic rodents, while Projects 1&4 clarify cellular mechanisms in transmitter biosynthesis and release, and exploit ex vivo biological materials from Projects 1&2 & Core C for phenotyping. A crucial theme is human genomic DNA resequencing to define the spectrum of allelic variation at loci governing sympathetic activity, and then probing the functional role of such variants. Studies in human twin pairs probe the genetic basis of heritable alterations in autonomic activity (Projects 1&2; Core C), and each Project (1&5) participates in phenotyping unique human candidate autonomic SNPs & haplotypes derived by Cores C&D. Already, significant, novel genetic associations have emerged at candidate loci. 6 Core facilities provide standardized human phenotypes and biological samples, cell populations, signal probes, genotyping, informatics, catecholamine and vasoactive peptide assays, and imaging. Using molecular biologic and informatic tools, the program aims to achieve a new level of understanding of the dynamic complexity of the sympathetic neuroeffector junction, and how its components lead to heritable changes in blood pressure, and ultimately to human hypertension. The Program thus represents a unique opportunity to define the genetic basis of common variations in human autonomic function governing blood pressure regulation.